Several previous studies have shown that 1 to 2 weeks of treatment with ethanol elicits tolerance to several effects produced by ethanol and cross-tolerance to nicotine-induced hypothermia. Similarly, short-term, high-dose nicotine treatment produces tolerance to nicotine and cross-tolerance to ethanol-induced hypothermia. In the studies reported here, C57BL/6 mice were force-fed ethanol, nicotine, or an ethanol/nicotine combination in the drinking water for 6 months. All of the chronic drug-treated mice developed tolerance to ethanol as measured by open-field activity, body temperature, and sleep-time tests. Ethanol tolerance is due, in part, to enhanced metabolism and reduced CNS sensitivity in the two ethanol-treated groups but only to reduced CNS sensitivity in the nicotine-treated group. Similar levels of tolerance to nicotine developed in those two groups that were nicotine-treated, but no tolerance to nicotine was seen in those animals treated with ethanol alone. The tolerance to nicotine may be related to an upregulation of brain (cortex, hippocampus, and hypothalamus) [3H]-nicotine binding, but ethanol tolerance is not readily explained by changes in the number of the brain high affinity nicotine binding sites.